Alcohol is one of the most widely used drugs in the U.S. and long-term abuse is devastating to individuals and society. Unfortunately, few therapeutics are available to treat the effects of alcohol addiction and the molecular mechanisms causing long-term abuse are still unclear. To identify novel genes that regulate ethanol sensitivity, we conducted a genetic screen in Drosophila melanogaster and identified a mutation in the Ras suppressor 1 (Rsu1)-encoding icarus (ics) gene. Fly strains carrying a mutation in the ics gene are resistant to the activating and sedating effects of alcohol. In this proposal, I hypothesize that ics is required in the CNS to mediate alcohol-induced responses and works through the integrin and EGFR signaling pathways to exert its effect. In this proposal, I will test hypothesis using genetic, biochemical and behavioral approaches to elucidate the molecular role of ics in regulating alcohol-induced responses. In aim 1 I will determine whether ics is important in the adult central nervous system for normal alcohol responses. In aim 2, to determine whether ics exerts its effect through the integrin and EGFR/ERK pathways, I will test genetic interactions between ics and mutants in these receptors and their downstream signaling genes, and ask whether those mutations modify the ics ethanol- resistance. Lastly, to identify the neurocircuit in the fly brain affecting alcohol- induced behaviors, I will generate novel enhancer-Gal4 lines with specific expression in the fly brain, and assess if they affect alcohol responses. In addition, I will test whether inhibition of ics in these Gal4 lines affects alcohol hyperactivity or sedation using RNAi mediated knockdown. Findings from this proposal will improve our comprehension of the molecular mechanism(s) of alcohol behavioral responses and help to create better treatments for addiction. PUBLIC HEALTH RELEVANCE: Alcoholism is a devastating disorder that significantly contributes to mortality, disability, and to healthcare costs. The goal of the proposed research is to characterize the role of the ics gene, encoding a Ras tumor suppressor associated with human alcohol abuse, in alcohol-induced behaviors in Drosophila. In conducting this research, we hope to identify risk factors for the development of alcoholism, as well as provide leads for the development of new therapeutic strategies aiding in the treatment of alcohol use disorders.